This invention relates to compositions useful in the preparation of radiodiagnostic agents for use in imaging and assay procedures. More particularly, it relates to compositions and processes used in preparing improved technetium-based tissue imaging agents.
Scintigraphic skeletal imaging and similar radiographic techniques for visualizing other tissues are finding ever-increasing application in biological and medical research and in diagnostic procedures. Generally, scintigraphic procedures involve the preparation of radioactive agents which, upon introduction into a biological subject, become localized in specific organs, tissues, or skeletal structures that are under study. When so localized, traces, plots, or scintiphotos of the distribution of the radiographic materials can be made by various radiation detectors, e.g., traversing scanners and scintilation cameras. The distribution and corresponding relative intensity of the detected radioactive material not only indicates the position occupied by the tissue in which the radionuclide is localized, but also indicates the presence of aberrations, pathological conditions, and the like.
In general, depending on the type of radionuclide used and the organ of interest, a scintigraphic imaging agent as used in a hospital comprises a radionuclide, a carrier agent designed to target the specific organ, various auxiliary agents which affix the radionuclide to the carrier, water or other delivery vehicles suitable for injection into, or aspiration by, the patient, physiologic buffers and salts, and the like. In most cases, the carrier attaches or complexes with the radionuclide and localizes the material in a location other than where the radionuclide itself would naturally concentrate in a biologic subject. However, certain radionuclides may be used without an additional carrier, such as thallium-201 (.sup.201 Tl), for myocardial localization, and technetium-99m (.sup.99 mTc), in pertechnetate form, for brain and thyroid imaging.
The tissue imaging agents of the instant invention incorporate technetium-99m as the radionuclide, complexed or coordinated with a tissue-specific carrier. This man-made radionuclide, which is formed in the radioactive decay of molybdenum-99, is commercially produced in "generators" by eluting a saline solution through a matrix containing molybdenum-99. The metastable technetium isotope in such eluates is found in the chemically-stable, oxidized, pertechnetate form (.sup.99 mTcO.sub.4.sup.-, hereinafter "pertechnetate-Tc99m"). However, the technetium in pertechnetate has a valence state of +7 and will not complex with the most commonly used carriers for radionuclide tissue imaging. This problem is easily overcome by reducing the technetium to a lower (+5, +4 and, most commonly, +3) oxidation state. Thus, technetium-labelled imaging agents are generally prepared by admixing pertechnetate-Tc99m isotonic saline solution with a technetium reductant (reducing agent). The ferrous and chromous salts, and the stannous salts (as are used in most commercial applications), of sulfuric and hydrochloric acid are known reductants for use in tissue imaging agents. For example, U.S. Pat. No. 3,983,227. Tofe and Francis, issued Sept. 28, 1976 discloses the use of such reducing salts, along with organophosphonate bone-seeking carriers, to prepare technetium-based skeletal imaging agents. U.S. Pat. No. 4,311,689, Ruddock, issued Jan. 19, 1982, describes the use of metallic tin as a reducing agent for pertechnetate, in tissue imaging compositions. Similarly, U.S. Pat. No. 4,314,986, Ruddock, issued Feb. 9, 1982, describes the use of metallic tin, and a soluble salt of a metal below tin on the electrochemical series, in tissue imaging compositions.
Such technetium-containing scintigraphic imaging agents are known to be unstable in the presence of oxygen, primarily since oxidation of the reductant and/or the technetium destroys the reduced technetium/targeting carrier complex. Accordingly, imaging agents are generally made oxygen-free by saturating the compositions with oxygen-free nitrogen gas or by preparing the agents in an oxygen-free atmosphere. Stabilization of imaging agents can also be achieved through chemical means. U.S. Pat. No. 4,232,000. Fawzi, issued Nov. 4, 1980, discloses the use of gentisyl alcohol as a stabilizer for technetium imaging agents. Similarly, U.S. Pat. No. 4,233,284, Fawzi, issued Nov. 11, 1980, discloses the use of gentisic acid as a stabilizer. German Offenlegungsschrift No. 2,618,337. Tofe, published Nov. 11, 1976, discloses the use of ascorbic acid and erythorbic acid as stabilizers with technetium imaging agents. U.S. patent application Ser. No. 387,138, Fawzi, et al., filed June 10, 1982, discloses the use of reductate stabilizers such as reductic acid, methyl reductic acid, and 6-bromo-6-deoxyascorbic acid, in imaging agents. European Patent Application Publication No. 46,067, Brockas, et al., published Feb. 17, 1982, describes compositions for use in tissue imaging that contain metallic tin or stannous salts as pertechnetate reducing agents together with nitrate or nitrite stabilizers.
It has now been discovered that the combination of metallic tin and certain stabilizing compounds is an effective reducing system for use in technetium-based tissue imaging compositions. Thus, the combination of tin metal and stabilizer reduces the technetium in commercially produced technetium-Tc99m solutions and maintains the technetium in a reduced state so as to allow formation of stable and useful complexes with tissue-specific carriers. (While the stabilizing compounds can, themselves, serve as tissue-specific carriers, additional carrier compounds are preferably included in the compositions of this invention.) The tissue imaging agents thereby formed have use characteristics superior to those of agents containing stannous salts alone, stannous salts and stabilizers, metallic tin alone, or metallic tin and nitrate or nitrite salts, with respect to chemical stability of the technetium/carrier complex and/or biologic performance.
The combination of tin metal and stabilizer can also be used in in vitro assay procedures such as radioimmunoassay (RIA). RIA allows the measurement of picogram (10.sup.-12 gram) quantities of antigens through labelling such antigens with a radioisotope. RIA procedures are described in Hunter, "Radioimmunoassay," Handbook of Experimental Immunology, Vol. 1, 2nd ed., (Wein, editor), 17.1-17.36 (1973). As an alternative to RIA procedures that use radioisotopes such as 1.sup.131 and 1.sup.125, antigens can be labelled with technetium-99m, prepared from commercially-available pertechnetate-Tc99m solutions through reduction by the tin metal/stabilizer compositions of the present invention.